In recent years, in accordance with the progress of immunology and science of transfusion, a blood component transfusion, in which only a blood component required to treat a particular disease is transfused, is now increasingly carried out in place of the conventional whole blood transfusion. The blood component transfusion is a therapy which is desirable because the burden on a patient receiving transfusion can be alleviated, and because it ensures a high treatment efficacy. various types of blood products, such as concentrated red cells (CRC), concentrated platelet cells (PC) and platelet-poor plasma (PPP), are employed in the blood component transfusion, and are prepared by subjecting donated whole blood to centrifugation. It has become apparent, however, that blood products obtained by centrifugation separation contain leukocytes in high concentration, and that side effects of transfusion are caused by the contained leukocytes. Side effects of transfusion include not only relatively mild side effects, such as headache, nausea, chilliness and nonhemolytic feverish reaction, but also serious side effects. Particularly with respect to the latter, when a transfusion recipient has an immunopathy, transfusion is likely to cause serious side effects, such as graft versus host (GVH) reaction, in which transfused leukocytes attack the skin and internal organs of the transfusion recipient, infections by viruses present in the leukocytes, e.g., cytomegalovirus infection, and allosensitization. The above-mentioned side effects of transfusion reactions can be effectively prevented by capturing and removing the leukocytes contained in the blood products.
Generally, blood products for use in transfusion, such as whole blood and a red cell product, contain 10.sup.7 leukocytes per ml. It is recognized that the number of leukocytes injected into a recipient at one transfusion must be limited to about 100,000,000 or less for avoiding relatively mild side effects, such as headache, nausea, chilliness and feverish reaction. To meet this requirement, leukocytes must be removed from a blood product to a level of 10.sup.-1 to 10.sup.-2 or less in terms of a leukocyte residual ratio. For preventing allosensitization and viral infections, however, leukocytes must be removed from a blood product to a level of 10.sup.-4 to 10.sup.-6 or less, in terms of a leukocyte residual ratio.
The methods for removing leukocytes from a blood product can generally be classified into two methods. One is a method in which leukocytes are separated by a centrifugation, taking advantage of a difference in specific gravity. The other is a filtering method in which leukocytes are removed by filtration, using a filter comprising as a filter material a fibrous porous medium, such as a non-woven fabric, or a porous article having a three-dimensional network of continuous pores. In particular, the filtering method is widely employed due to the advantages that leukocytes can be removed with high efficiency, handling is easy and cost can be reduced.
In recent years, intensive studies have been made to develop filter apparatus for removing leukocytes. Especially, it is strongly desired in the art to develop a filter apparatus which not only has the ability to effectively remove leukocytes but also is free from a pressure loss increase due to blood cell clogging, so that blood filtration can be continuously performed without interruption.
It is known that removal of leukocytes is mainly attained by adhesion. Accordingly, the difference in leukocyte removal efficiency between filter materials which are comprised of the same material and have similar surfaces, is considered to be dependent on the degree of collision frequency between the filter materials and leukocytes. For improving the leukocyte removal efficiency, it is desired that the surface of a filter material, to which leukocytes will adhere, be larger so that the collision frequency is increased between the filter material and leukocytes. Actually, an increase of the surface area of a filter material is generally accomplished by the employment of extremely fine fibers having an average fiber diameter of about 1 to 3 .mu.m, when the filter material is comprised of a fibrous, porous medium, such as a non-woven fabric (see Japanese Patent Application Laid-Open Specification No. 60-193468/1985). On the other hand, when the filter material is comprised of a porous article having a uniform average pore diameter, the increase of the surface area is generally accomplished by the employment of porous articles having an average pore diameter as small as from 5 to 20 .mu.m (see Japanese Patent Application Published Specification No. 63-26089/1988 and Japanese Patent Application Laid-Open Specification No. 3-173825/1991).
When a filter material comprised of a fibrous, porous medium, such as a non-woven fabric is used, for improving the leukocyte removal efficiency per volume of a filter apparatus for removing leukocytes, it has generally been required either to increase the packing density of the filter material so as to substantially increase the amount of the filter material, or to employ a fibrous, porous medium having a smaller fiber diameter. The upper limit of the packing density of the filter material is about 0.4 g/cm.sup.3. Beyond this upper limit, packing of, for example, a non-woven fabric, into a filter container becomes difficult due to the resiliency of the non-woven fabric. If a hot compression is performed to avoid the resiliency, the non-woven fabric is collapsed into a film form, which is no longer useful as a filter material. Therefore, for improving the leukocyte removal efficiency, it has been necessary to adopt either a method in which the amount of the filter material is increased while keeping the packing density thereof at 0.4 g/cm.sup.3 or less, or a method in which a filter material comprising fibers having a smaller average fiber diameter is employed. When a porous article having a uniform average pore diameter is used as a filter material, it has been necessary to keep the pore diameter as small as possible, for improving the leukocyte removal efficiency. In any of these measures for improving the leukocyte removal efficiency, however, there has been a problem that the improvement of the leukocyte removal efficiency is inevitably accompanied by an increase of a pressure loss in the filter material during the passage of a blood product, so that the filtration rate decreases significantly before completion of the filtration of a predetermined amount of the blood product.
With respect to a spongy structure as a porous article, Japanese Patent Application Laid-Open Specification No. 1-224324/1989 discloses a structure having a bubble point of from 0.08 to 0.3 kg/cm.sup.2, which is described as being a leukocyte separator free from the danger of clogging with leukocytes. The present inventors have examined the leukocyte separator. As a result, they have found that the ability of the separator to remove the leukocytes contained in a blood product is only about 10.sup.-2 to 10.sup.-3 in terms of a leukocyte residual ratio. When a porous article having an extremely small average pore diameter is employed in order to attain a leukocyte residual ratio of 10.sup.-4, it has had drawbacks. That is, a porous article having an optimal average pore diameter can exhibit the same degree of leukocyte removal efficiency as attained by a non-woven fabric, even though the thickness of the porous article is a small fraction of that of the non-woven fabric, so that an advantageous means can be provided for attaining miniaturization, however, a porous article capable of exhibiting a leukocyte residual ratio of 10.sup.-4 disadvantageously suffers from a pressure loss increase due to clogging with leukocytes. This clogging causes the blood filtration rate to be extremely low, as in the use of a non-woven fabric having an extremely small diameter.
EP 0406485 A1 discloses a filter apparatus for removing leukocytes which is allegedly capable of solving the above-mentioned drawbacks. The filter apparatus is packed with a porous article as a filter material which has an average pore diameter gradient such that the average pore diameter is decreased in a flow direction in which blood is adapted to be flowed from an upstream end portion to a downstream end portion of the porous article, in order to avoid a blood cell clogging of the upstream end surface of the porous article. However, although some drawbacks, such as pressure loss increase and filtration time prolongation due to blood cell clogging, can be overcome by the use of the leukocyte-removing filter apparatus disclosed in EP 0406485 A1, this apparatus cannot satisfactorily prevent leakage of lymphocytes which have a relatively low adherence and a relatively small size among leukocytes, so that the leukocyte residual ratio attained by the apparatus is disadvantageously as high as about 10.sup.-1 to 10.sup.-2.
As described above, no leukocyte-removing filter apparatus has heretofore been proposed which exhibits a leukocyte removal efficiency as excellent as 10.sup.-4 or less in terms of a leukocyte residual ratio, and which ensures smooth blood filtration.
Miniaturization of a filter apparatus is an important theme to be attained regarding a leukocyte-removing filter apparatus, like the improvement of a leukocyte removal efficiency and the attainment of a smooth blood filtration. Usually, after completion of the filtration operation to remove leukocytes, the blood product remaining inside the filter apparatus is discarded together with the filter apparatus. Therefore, to minimize the waste of the blood product, a filter apparatus having a small hold-up volume is desired. The terminology "hold-up volume" used herein means the volume of the whole space inside a leukocytes removing filter apparatus. Generally, it is desired that the proportion of the blood product discarded with a filter apparatus be limited to a level as low as 10-15% or less. For meeting this, it is desired that the filter apparatus be of such a small size as to have a hold-up volume as small as 35 ml or less per unit of whole blood or a red cell product or as small as 20 ml or less per 5 units of a platelet product.
In addition, there has been a problem that an increase in the surface area of a filter material and in the hold-up volume of a leukocyte-removing filter apparatus is likely to cause the recovery of desired non-leukocyte blood components, such as red cells and platelets, to be poor. In particular, platelets have high adherence, and hence, the employment of a filter material having too large a surface area causes the recovery of platelets to be extremely poor.